An infrastructure for secure data sharing: a clinical data implementation.

Objective: To address database interoperability challenges to improve collaboration among disparate organizations. Materials and Methods: We developed a lightweight system to allow broad but well-controlled data sharing while preserving local data protection policies. We used 2 NIST-developed technologies-Next-generation Database Access Control (NDAC) and the Data Block Matrix (DBM)-to create a proof-of-concept system called the Secure Federated Data Sharing System (SFDS). NDAC controls access to database resources down to the field level based on attributes assigned to users. The DBM manages and shares authoritative user-attribute assignments across a federation of organizations, implemented using a modified open-source permissioned blockchain, to manage and share authoritative user-attribute assignments across a federation of organizations. We used synthetic data to demonstrate a clinical research data-sharing use case using the SFDS. Results: We demonstrated, through consent, the onboarding of previously unknown users into NDAC via assignments to their DBM-validated attributes, allowing those users policy-preserving access to local database resources. The SFDS main system components-NDAC and DBM-also showed excellent performance metrics. Discussion: The SFDS provides a generic data-sharing infrastructure that effectively and securely achieves data-sharing objectives. It is completely transparent to the otherwise normal business operations of participating organizations. It requires no changes to database management systems or existing methods of authenticating and authorizing local user access to local resources. Conclusion: This efficiency, flexibility of deployment, and granularity of control make this new infrastructure solution practical for meeting the data-sharing and protection objectives of the clinical research community.

Life Satisfaction and Negative Affect Among Trans Men, Trans Women, and Nonbinary Individuals in a U.S. National Sample.

Purpose: Transgender and nonbinary individuals often have limited educational and economic resources, lack social capital such as family and community support, and face discrimination. These factors are likely to have negative consequences for subjective well-being of transgender individuals. Yet, there is limited research using a national sample and comparing trans women, trans men, and nonbinary individuals. This study examined the impact of social support, social belonging, transgender connectedness, and discrimination on trans and nonbinary individuals' life satisfaction and negative affect. Methods: We used data from TransPop 2016-2018, the first survey conducted on a national probability sample of the transgender population in the United States. We focused on measures of life satisfaction and negative affect and their predictors, including social belonging, transgender connectedness, and everyday discrimination. Results: We found that trans men, trans women, and nonbinary individuals had lower life satisfaction and higher negative affect than cisgender heterosexual individuals. Social belonging had a positive effect on trans men and trans women's life satisfaction, whereas it had a negative effect on trans men and nonbinary individuals' negative emotion. While family support had a positive effect on trans men's life satisfaction, social support had mixed effects on nonbinary individuals' life satisfaction and negative affect. Finally, everyday discrimination had a negative influence on life satisfaction although there was variation by gender identity and dependent measure. Conclusion: Different factors predicted life satisfaction and negative affect of trans men, trans women, and nonbinary people. Thus, a one-size-fits-all model of trans and nonbinary subjective well-being does not work.

Will clinical standards not be part of the choir? Harmonization between the HL7 gender harmony project model and the NASEM measuring sex, gender identity, and sexual orientation report in the United States.

OBJECTIVES: To propose an approach for semantic and functional data harmonization related to sex and gender constructs in electronic health records (EHRs) and other clinical systems for implementors, as outlined in the National Academies of Sciences, Engineering, and Medicine (NASEM) report Measuring Sex, Gender Identity, and Sexual Orientation and the Health Level 7 (HL7) Gender Harmony Project (GHP) product brief "Gender Harmony-Modeling Sex and Gender Representation, Release 1." MATERIALS AND METHODS: Authors from both publications contributed to a plan for data harmonization based upon fundamental principles in informatics, including privacy, openness, access, legitimate infringement, least intrusive alternatives, and accountability. RESULTS: We propose construct entities and value sets that best align with both publications to allow the implementation of EHR data elements on gender identity, recorded sex or gender, and sex for clinical use in the United States. We include usability- and interoperability-focused reasoning for each of these decisions, as well as suggestions for cross-tabulation for populations. DISCUSSION AND CONCLUSION: Both publications agree on core approaches to conceptualization and measurement of sex- and gender-related constructs. However, some clarifications could improve our ability to assess gender modality, alignment (or lack thereof) between gender identity and assigned gender at birth, and address both individual-level and population-level health inequities. By bridging the GHP and NASEM recommendations, we provide a path forward for implementation of sex- and gender-related EHR elements. Suggestions for implementation of gender identity, recorded sex or gender, and sex for clinical use are provided, along with semantic and functional justifications.

Evaluating the Use of a Two-Step Gender Identity Measure in the 2018 General Social Survey.

In 2018, the General Social Survey (GSS) asked some respondents for their sex assigned at birth and current gender identity, in addition to the ongoing practice of having survey interviewers code respondent sex. Between 0.44% and 0.93% of the respondents who were surveyed identified as transgender, identified with a gender that does not conventionally correspond to the sex they were assigned at birth, or identified the sex they were assigned at birth inconsistently with the interviewer's assessment of respondent sex. These results corroborate previous estimates of the transgender population size in the United States. Furthermore, the implementation of these new questions mirrors the successful inclusion of other small populations represented in the GSS, such as lesbian, gay, and bisexual people, as well as Muslims, Buddhists, and Hindus. Data on transgender and gender-nonconforming populations can be pooled together over time to assess these populations' attitudes, beliefs, behaviors, and social inequality patterns. We identified inconsistencies between interviewer-coded sex, self-reported sex, and gender identity. As with the coding of race in the GSS, interviewer-coded assessments can mismatch respondents' self-reported identification. Our findings underscore the importance of continuing to ask respondents to self-report gender identity separately from sex assigned at birth in the GSS and other surveys.

Beyond the Castro: the role of demographics in the selection of gay and lesbian enclaves.

Although some qualitative research has noted differences in gay and lesbian enclaves based on characteristics such as race and sex, in this article, we draw upon quantitative data from the U.S. Census to demonstrate the manner in which enclave formation is affected by the interaction of sexual orientation and other demographic characteristics (such as sex, race, age, and income). We focus our attention on enclaves located in three counties in the San Francisco Bay Area: San Francisco County, Alameda County, and Sonoma County as one example. Even though these spaces fall within close proximity to one another and share similar geographic appeal, our analyses indicate that these enclaves are far from homogenous in terms of the demographic composition of their inhabitants. These quantitative analyses provide further support to past qualitative findings, as well as highlight additional distinctions in the manner in which demographics affect enclave selection. We supplement our demographic analyses with supporting field research and interviews, further highlighting both the variation and the commonalities of these enclaves. Overall, our findings promote an expansion of the understanding how intersecting demographic characteristics affect selection of a particular enclave and what may constitute a gay enclave.

Developmental competence of human in vitro aged oocytes as host cells for nuclear transfer.

BACKGROUND: Improving human nuclear transfer (NT) efficiencies is paramount for the development of patient-specific stem cell lines, although the opportunities remain limited owing to difficulties in obtaining fresh mature oocytes. METHODS: Therefore, the developmental competence of aged, failed-to-fertilize human oocytes as an alternate cytoplasmic source for NT was assessed and compared with use of fresh, ovulation-induced oocytes. To further characterize the developmental potential of aged oocytes, parthenogenetic activation, immunocytochemical analysis of essential microtubule proteins involved in meiotic and mitotic division, and RT-PCR in single oocytes (n = 6) was performed to determine expression of oocyte-specific genes [oocyte-specific histone 1 (H1FOO), growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), zygote arrest 1 (ZAR1)] and microtubule markers [nuclear mitotic arrest (NuMA), minus-end directed motor protein HSET and the microtubule kinesin motor protein EG5]. RESULTS: For NT, enucleation and fusion rates of aged oocytes were significantly lower compared with fresh oocytes (P < 0.05). Cleavage rates and subsequent development were poor. In addition, parthenote cleavage was low. Immunocytochemical analysis revealed that many oocytes displayed aberrant expression of NuMA and EG5, had disrupted meiotic spindles and tetrapolar spindles. One of the six oocytes misexpressed GDF9, BMP15 and ZAR1. Two oocytes expressed EG5 messenger RNA (mRNA), and HSET and NuMA were not detectable. RT-PCR of mRNA for oocyte specific genes and microtubule markers in single aged oocytes. CONCLUSIONS: Thus, aneuploidy and spindle defects may contribute to poor parthenogenetic development and developmental outcomes following NT.

Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer's disease: evidence of effect modification by apolipoprotein E (APOE).

Insulin degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid peptide implicated in Alzheimer's disease (AD). We reexamined data on five previously reported IDE polymorphisms stratifying the analysis by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele. Three IDE variants were associated with AD within epsilon4-negative subjects (genotype exact test P-values < or =0.02). A haplotype containing the minor variant at each of these sites represented an estimated 4.2% of case haplotypes versus 12.3% of control haplotypes among epsilon4-negative subjects. Lack of this minor haplotype may be predictive of AD, potentially explaining some fraction of disease within subjects without the APOE epsilon4 risk allele. Confirmation of this finding with a larger sample of cases and controls is warranted.

Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice.

Ezetimibe (SCH58235) is a potent, selective, cholesterol absorption inhibitor. The objective of this study was to determine whether ezetimibe reduces plasma cholesterol and inhibits atherogenesis in apolipoprotein E knockout (apoE-/-) mice. Cholesterol absorption was inhibited by >90% at doses of ezetimibe >3 mg/kg in apoE-/- mice. Atherosclerosis and lipoprotein changes were determined in apoE-/- mice fed a high-fat (0.15% cholesterol) "western" diet, a low-fat (0.15% cholesterol) diet, or a semisynthetic cholesterol-free diet with or without ezetimibe (5 mg/kg per day) for 6 months. Ezetimibe reduced plasma cholesterol levels from 964 to 374 mg/dL, from 726 to 231 mg/dL, and from 516 to 178 mg/dL in the western, low-fat, and cholesterol-free diet groups, respectively. The reductions occurred in the very low density and low density lipoprotein fractions, whereas high density lipoprotein cholesterol levels were increased by ezetimibe treatment. Ezetimibe reduced aortic atherosclerotic lesion surface area from 20.2% to 4.1% in the western diet group and from 24.1% to 7.0% in the low-fat cholesterol diet group. Ezetimibe reduced carotid artery atherosclerotic lesion cross-sectional area by 97% in the western and low-fat cholesterol groups and by 91% in the cholesterol-free group. Ezetimibe inhibits cholesterol absorption, reduces plasma cholesterol, increases high density lipoprotein levels, and inhibits the progression of atherosclerosis under western, low-fat, and cholesterol-free dietary conditions in apoE-/- mice. Although apoE-/- mice are more hypercholesterolemic than are humans and low density lipoprotein reductions with ezetimibe are not as pronounced clinically, ezetimibe may inhibit atherogenesis in individuals consuming restricted-fat or western diets.

Analysis of mitotic microtubule-associated proteins using mass spectrometry identifies astrin, a spindle-associated protein.

We purified microtubules from a mammalian mitotic extract and obtained an amino acid sequence from each microtubule-associated protein by using mass spectrometry. Most of these proteins are known spindle-associated components with essential functional roles in spindle organization. We generated antibodies against a protein identified in this collection and refer to it as astrin because of its association with astral microtubule arrays assembled in vitro. Astrin is approximately 134 kDa, and except for a large predicted coiled-coil domain in its C-terminal region it lacks any known functional motifs. Astrin associates with spindle microtubules as early as prophase where it concentrates at spindle poles. It localizes throughout the spindle in metaphase and anaphase and associates with midzone microtubules in anaphase and telophase. Astrin also localizes to kinetochores but only on those chromosomes that have congressed. Deletion analysis indicates that astrin's primary spindle-targeting domain is at the C terminus, although a secondary domain in the N terminus can target some of the protein to spindle poles. Thus, we have generated a comprehensive list of major mitotic microtubule-associated proteins, among which is astrin, a nonmotor spindle protein.

Alpha-chymotrypsin catalysis in imidazolium-based ionic liquids.

The transesterification reaction of N-acetyl-L-phenylalanine ethyl ester with 1-propanol catalyzed by alpha-chymotrypsin was examined in the ionic liquids 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF(6)]) and 1-octyl-3-methylimidazolium hexafluorophosphate ([omim][PF(6)]), and in combination with supercritical carbon dioxide (SC-CO(2)). The activity of alpha-chymotrypsin was studied to determine whether trends in solvent polarity, water activity, and enzyme support properties, observed with this enzyme in conventional organic solvents, hold for the novel environment provided by ionic liquids. alpha-Chymotrypsin freeze-dried with K(2)HPO(4), KCl, or poly(ethylene glycol) demonstrated no activity in [bmim][PF(6)] or [omim][PF(6)] at very low water concentrations, but moderate transesterification rates were observed with the ionic liquids containing 0.25% water (v/v) and higher. However, the physical complexation of the enzyme with poly(ethylene glycol) or KCl did not substantially stimulate activity in the ionic liquids, unlike that observed in hexane or isooctane. Activities were considerably higher in [omim][PF(6)] than [bmim][PF(6)]. Added water was not necessary for enzyme activity when ionic liquids were combined with SC-CO(2). These results indicate that [bmim][PF(6)] and [omim][PF(6)] provide a relatively polar environment, which can be modified with nonpolar SC-CO(2) to optimize enzyme activity.

Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function.

1. Ezetimibe potently inhibits the transport of cholesterol across the intestinal wall, thereby reducing plasma cholesterol in preclinical animal models of hypercholesterolemia. The effect of ezetimibe on known absorptive processes was determined in the present studies. 2. Experiments were conducted in the hamster and/or rat to determine whether ezetimibe would affect the absorption of molecules other than free cholesterol, namely cholesteryl ester, triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid. In addition, to determine whether exocrine pancreatic function is involved in the mechanism of action of ezetimibe, a biliary anastomosis model, which eliminates exocrine pancreatic function from the intestine while maintaining bile flow, was established in the rat. 3. Ezetimibe reduced plasma cholesterol and hepatic cholesterol accumulation in cholesterol-fed hamsters with an ED(50) of 0.04 mg kg(-1). Utilizing cholesteryl esters labelled on either the cholesterol or the fatty acid moiety, we demonstrated that ezetimibe did not affect cholesteryl ester hydrolysis and the absorption of fatty acid thus generated in both hamsters and rats. The free cholesterol from this hydrolysis, however, was not absorbed (92 - 96% inhibition) in the presence of ezetimibe. Eliminating pancreatic function in rats abolished hydrolysis of cholesteryl esters, but did not affect the ability of ezetimibe to block absorption of free cholesterol (-94%). Ezetimibe did not affect the absorption of triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid in rats. 4. Ezetimibe is a potent inhibitor of intestinal free cholesterol absorption that does not require exocrine pancreatic function for activity. Ezetimibe does not affect the absorption of triglyceride as a pancreatic lipase inhibitor (Orlistat) would, nor does it affect the absorption of vitamin A, D or taurocholate, as a bile acid sequestrant (cholestyramine) would.

The chromokinesin Kid is necessary for chromosome arm orientation and oscillation, but not congression, on mitotic spindles.

Chromokinesins have been postulated to provide the polar ejection force needed for chromosome congression during mitosis. We have evaluated that possibility by monitoring chromosome movement in vertebrate-cultured cells using time-lapse differential interference contrast microscopy after microinjection with antibodies specific for the chromokinesin Kid. 17.5% of cells injected with Kid-specific antibodies have one or more chromosomes that remain closely opposed to a spindle pole and fail to enter anaphase. In contrast, 82.5% of injected cells align chromosomes in metaphase, progress to anaphase, and display chromosome velocities not significantly different from control cells. However, injected cells lack chromosome oscillations, and chromosome orientation is atypical because chromosome arms extend toward spindle poles during both congression and metaphase. Furthermore, chromosomes cluster into a mass and fail to oscillate when Kid is perturbed in cells containing monopolar spindles. These data indicate that Kid generates the polar ejection force that pushes chromosome arms away from spindle poles in vertebrate-cultured cells. This force increases the efficiency with which chromosomes make bipolar spindle attachments and regulates kinetochore activities necessary for chromosome oscillation, but is not essential for chromosome congression.

Are memories for stimulus-stimulus associations or stimulus-response associations responsible for serial-pattern learning in rats?

Previous research has provided convincing evidence that rats can learn to anticipate the individual elements of a stimulus series consisting of differing amounts of food reinforcement. Rats prepared with lesions of the dorsal striatum or hippocampus were initially trained to acquire a three-element series consisting of 21 sucrose pellets, followed by 0- and 7-pellets (Noyes standard), respectively. During the initial 30 days of training, the animals were run in two adjacent runways; the runways included either of a white, rough runway or a black, smooth runway as additional series cues. Thus, training included both floor (S-R) cues and the series (inter-item memory) cues. Anticipation was defined as faster running on the 21- than on the 7-pellet element and 7- than on the 0-pellet element. While anticipation developed more slowly in the lesion groups than in the control group, all animals eventually demonstrated the ability to track the elements of the series. Reversal of the floor cues disrupted tracking in the hippocampus-lesioned and control animals; dorsal striatum-lesioned rats were also affected but did continue tracking. As a final test, shifting the order of the series produced a marked disruption in performance in the dorsal striatum-lesioned rats but not in the hippocampus-lesioned or control rats. The results are consistent with the proposal that integrated neural mediation is required for anticipation, with a system that includes the dorsal striatum necessary for the promotion of a reinforced approach response and a system that includes the hippocampus necessary for associating and temporarily maintaining an internal record of the different elements of the stimulus series.

The cholesterol absorption inhibitor, ezetimibe, decreases diet-induced hypercholesterolemia in monkeys.

Ezetimibe (1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone) potently and selectively inhibits the intestinal absorption of cholesterol, thereby reducing plasma cholesterol in preclinical models of hypercholesterolemia. In rhesus monkeys fed a diet containing 375 mg/day of cholesterol, 0.1 mg/kg of ezetimibe completely prevented the doubling of plasma cholesterol normally induced under these dietary conditions (ED(50)=0.0005 mg/kg). Low-density lipoprotein cholesterol (LDL) was dose-dependently reduced, while high-density lipoprotein cholesterol (HDL) and plasma triglyceride were unchanged. A single dose of an ezetimibe analog administered to cynomolgus monkeys fed a single cholesterol-containing meal caused a significant reduction (-69%) of cholesterol in chylomicrons during the postprandial phase without affecting triglyceride content. In rhesus monkeys, apolipoprotein (apo) B(48) concentrations in chylomicrons did not differ between control and the ezetimibe analog, but apo B(100) was significantly reduced in LDL (-41%). These data indicate that these cholesterol absorption inhibitors reduce cholesterol content in chylomicrons, which indirectly leads to a decrease in LDL cholesterol and particle number.

Chromosome movement in mitosis requires microtubule anchorage at spindle poles.

Anchorage of microtubule minus ends at spindle poles has been proposed to bear the load of poleward forces exerted by kinetochore-associated motors so that chromosomes move toward the poles rather than the poles toward the chromosomes. To test this hypothesis, we monitored chromosome movement during mitosis after perturbation of nuclear mitotic apparatus protein (NuMA) and the human homologue of the KIN C motor family (HSET), two noncentrosomal proteins involved in spindle pole organization in animal cells. Perturbation of NuMA alone disrupts spindle pole organization and delays anaphase onset, but does not alter the velocity of oscillatory chromosome movement in prometaphase. Perturbation of HSET alone increases the duration of prometaphase, but does not alter the velocity of chromosome movement in prometaphase or anaphase. In contrast, simultaneous perturbation of both HSET and NuMA severely suppresses directed chromosome movement in prometaphase. Chromosomes coalesce near the center of these cells on bi-oriented spindles that lack organized poles. Immunofluorescence and electron microscopy verify microtubule attachment to sister kinetochores, but this attachment fails to generate proper tension across sister kinetochores. These results demonstrate that anchorage of microtubule minus ends at spindle poles mediated by overlapping mechanisms involving both NuMA and HSET is essential for chromosome movement during mitosis.

Integrating theory and practice. Conceptual frameworks of the CEFP.

In this article, we describe how different conceptual frameworks contributed to the design, development, and implementation of the Collaborative Evaluation Fellows Project (CEFP). These frameworks are the following: utilization-focused evaluation (Patton, 1997); evaluative inquiry for learning in organizations (Preskill & Torres, 1999); and collaboration for a change (Himmelman, 1994). In addition, we explain how The Program Evaluation Standards (Joint Committee on Standards for Educational Evaluation, 1994) provided criteria for implementing and assessing the evaluation studies conducted through the CEFP. We conclude the article with examples of how the CEFP has changed the way American Cancer Society staff members and volunteers think about and conduct evaluations.

The Collaborative Evaluation Fellows Project. Background and overview of the model.

The Collaborative Evaluation Fellows Project (CEFP) of the American Cancer Society builds organizational capacity for evaluation by partnering with schools of public health to conduct local evaluation studies. This model was envisioned in response to the American Cancer Society's growing demand for program evaluation and the challenges of institutionalizing evaluation nationwide and at all levels of the organization. The CEFP also formalizes partnerships between the American Cancer Society and universities, and provides practical opportunities for public health graduate students and faculty. Working with an American Cancer Society evaluation facilitator and an advisory group, faculty and graduate students use a 15-step process to conduct evaluation studies at the local level. Students also can use these data for their master's these. The 15-step process is based on the utilization-focused evaluation approach and is designed to foster the use of evaluation findings by program stakeholders. The CEFP model has been implemented in American Cancer Society offices nationwide and has been replicated with another nonprofit health organization.

Evaluation use and the CEFP. Lessons from a case study.

The Collaborative Evaluation Fellows Project was designed to build the evaluation capacity of the American Cancer Society and to produce evaluations that would be used in decision making on the local to national levels. Is this kind of use occurring and has use become a means of institutionalizing evaluation? Data from site visits to six regional offices suggest some use of findings occurring, while other data clearly indicate that an evaluation ethos and evaluation practice are both taking hold within the organization.

Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease.

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.